WO1992015296A1

WO1992015296A1 - Remedy for renal diseases

Info

Publication number: WO1992015296A1
Application number: PCT/JP1992/000208
Authority: WO
Inventors: Takeshi Andoh; Itsuo Nagatomi
Original assignee: Fujisawa Pharmaceutical Co., Ltd.
Priority date: 1991-03-01
Filing date: 1992-02-26
Publication date: 1992-09-17
Also published as: CA2105291A1; KR930702972A; AU1337992A; MX9200869A; ZA921381B; EP0573652A4; TW197370B; EP0573652A1

Abstract

A remedy for renal diseases containing an amino acid derivative represented by general formula (I) or its salt as the active ingredient. In the said formula, R?1 represents optionally substituted lower alkyl, etc.; R?2 represents hydrogen or lower alkyl, or alternatively R?1 and R?2 form together with the adjacent nitrogen atom an optionally substituted heterocyclic group; R?3 represents hydrogen or lower alkyl; and R?4 represents lower alkyl.

Description

Harm

Disease therapeutic technology

The present invention relates to a therapeutic agent for renal disease containing an amino acid derivative or a salt thereof.

And this invention is based on amino acid derivatives or salts thereof. ? New uses for the treatment of diseases.

In more detail, the acid is a renal disease of an amino acid derivative or a salt thereof represented by the following structural formula (I) [for example, insufficiency, diabetic disease, inflammatory disease) (E.g. glomeruli ^ inflammation), nephrotic syndrome, drug-induced toxicity, renal edema, gout, hyperuricemia, etc.] .

Accordingly, an object of the present invention is to provide a therapeutic agent for a disease comprising an amino acid derivative or a salt thereof.

A further object of the present invention is to provide a pharmaceutical composition for treating renal disease, comprising an amino acid derivative or a salt thereof as an active ingredient. is there .

Furthermore, is the purpose of this invention in humans or animals? ? It is intended to provide the use of an amino acid derivative or a salt thereof for manufacturing a medicament for treating a disease.

A further object of the present invention is to provide a method for treating renal disease, which comprises administering an amino acid derivative or a salt thereof to a human or animal. is there . Background technology

The aminoic acid derivative of this cinnamon has renin inhibitory activity and is useful for treating hypertension such as essential hypertension, essential hypertension, malignant hypertension, and heart failure. This is known from the description in EP-A-301 189. Disclosure of the invention

The amino acid derivative used in the present invention is represented by the general formula (I).

(I)

[Wherein, R 丄 is an acyl group, a hydroxy group, a lower alkoxy group, an aryl group, a lower alkylthio group, and a group represented by the formula

(Wherein, R ⁵ represents hydrogen or an acyl group, and R ^σ represents hydrogen or a quaternary alkyl group, respectively) selected from the group consisting of: A lower alkyl group which may be substituted with a substituted substituent; an aryl / le group; or a lower alkyl group. An amino group which may be substituted with a substituent selected from the group consisting of:

R ² represents hydrogen or a lower alkyl group, or, together with R ¹ or an adjacent nitrogen atom, forms a lower alkyl group or a hydrid group; Loxy (lower) alkyl group, lower alkyl (lower) alkyl group, acyl (lower) alkyl group, oxo group and acyl group Forming a heterocyclic group which may be substituted with a substituent selected from the group consisting of: R ³ is hydrogen or a lower alkyl group,

R ⁴ represents a lower alkyl group]

In this description and in the claims, suitable examples of the various definitions that fall within the scope of the invention are set forth in detail below.

"Lower", unless otherwise indicated, shall mean a group having from 1 to 7 carbon atoms.

Preferred ¹ "lower alkyl groups" include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl ', isobutyl, and tertiary. Linear or branched alkyl groups such as butyl, pentyl, isopentyl, hexyl, methylhexyl, heptyl, etc. Is mentioned.

The preferred "acyl" portion of the "acyl group" and the "acyl (lower) alkyl group" is

, Ν— CO—, IT—CO— and IT—SO—

R [Wherein, R ⁷ and R ⁸ are each hydrogen; an aryl group; a cyclic σ (lower) alkyl group; a heterocyclic group; or a lower alkoxycarbonyl group. A lower alkyl group which may be substituted with a substituent selected from the group consisting of an alkyl group, a lower alkoxy group, an aryl group, and a heterocyclic group. Means or

R ¹ and R ° together with the adjacent nitrogen atom form a heterocyclic group which may be substituted by a lower alkyl group;

R ⁹ is an aryl group; a cyclo (lower) alkyl group; a lower alkoxy group and a mono or di (lower) alkylamino group A lower alkyl group which may be substituted with a substituent selected from a group selected from the group consisting of: a group consisting of a lower alkyl group and an aryl group; A lower alkoxy group which may be substituted with a substituent selected from the above.], Or an amino group, which may be protected. And amino acid residues.

Suitable "aryl groups" include groups such as phenyl, naphthyl, tolyl, xylyl, mesityl, cumenyl, and the like. Preferred among them is a phenyl group.

Suitable "cyclo mouth (lower) alkyl groups" include cyclopropyl, cyclobutyric, cyclopentyl, cyclohexyl and the like. The following groups can be mentioned.

Suitable "multiple of a suitable" heterocyclic group "rabbi of R 'and R ⁸ as a substituent of lower A Le key Le group R ⁷ your good beauty R ⁸ A "cyclic group" is a saturated or unsaturated monocyclic or unsaturated monocyclic or heterocyclic group containing at least one heteroatom such as a nitrogen atom, an oxygen atom or an iodo atom. Polycyclic heterocyclic groups, preferably 5-, or 6-membered heterocyclic groups containing N, 0 and 0 or S, are selected and most preferred among them. Those are morpholino, pyridyl and thiazolyl groups.

Is the ^one preferred "lower A Le breath Shea group" your good beauty "lower A Le breath over-le-ball double Le based on suitable ^Γ lower A Le breath death" part of the "main door key sheet , Ethoxy, bropoxy, isopro box, butoxy, isobutoxy, tertiary butoxy, ventilator, hexagon Shi Le O key is Yo will Do linear or such sheets include branched a Le co key sheet group, which we also to the to have good or to be al in the - c ₄ a And a alkoxy group.

Suitable heterocyclic groups j formed by R ⁷ , R ° and an adjacent nitrogen atom include morpholino, diolholino, and the like. One-year-olds or 1,1—dioxides, pyrrolidines, virazolizins, pipellinos, piperidinos, pipes Radical 1-yl, pyrrolin 1-yl, thiazolidine 1-3-yl, its 1- or 1- or 1-dioxy 1, 1, 4, 1, 4, 1, 2, 3, 1, 4 , 2, 3, 6 — tetrahydropyridine 1-yl, 1, 2, 3, 4 — tetrahydroisoquinolin 1-2-yl, 1 , 2,3,4 — Tetrahydroquinoline Kisamethylene Simino, 1, 4 Mouth [4..3.0.] Non-North 4-yl.

Suitable “mono or di (lower) alkylamino groups” include methylamino, ethylamino, propylamino, and i-amino. Sopropylamino, Butylamino, Isobutylamino, Dimethylamino, Methylethylamino, Methylylamino Examples include groups such as mino and methylamino.

Suitable “lower alkanol groups j” include holmilyl, acetyl, propionyl, butylyl, isobutylyl, norylyl, isonoryl Examples include groups such as lilyl, pinolyl, and 4-methyl valeryl.

Preferred amino acid residues j which may be protected with an amino group include glycyl, aranil, — aranil, valyl, and b. ISIL, ISOLOSIL, HISTIL, BROLIL, SERYL, THREENIL, SISTIL, FENARARANIL, ASPA Residues such as rutile, glutamyl, tributyl, etc., and each amino group of those residues is, for example, holmil, acetyl, prote. Substituted or unsubstituted lower alkoxy, phthaloyl, phthaloyl, such as pionyl, trifluoroacetyl, etc. Lower alkoxycarbonyl groups such as xylbonil and tertiary aminoxyloxycarbonyl, such as benzylbenzene , P—Tro Substituted or unsubstituted aryloxycarbonyl groups such as benzyloxycarbonyl, e.g., benzenesulfonyl, Substituted or unsubstituted allyl sulfonyl groups such as sil, nitro Protected by conventional N-protecting groups such as phenyl-sulfur radicals, for example, trialkyl, benzyl, etc. You may be.

Preferable examples of the above-mentioned acyl group include, for example, holmil, acetyl, propionyl, butylyl, isobutylyl, and butyl. Lower-alkanol groups such as relyl, iso-no-relyl, piper-roll, and 41-methyl-relyl, for example, methyl-aminose Mono or di (lower) alkylamino (lower) such as chill, methyl amino, or pionyl, dimethylaminobutyryl, etc. Low-alkoxy groups (lower) such as carbonyl groups, for example, methoxy acetyl, methoxy propylonyl, ethoxy propylion, etc. Lucanol group, for example, Benzoyl, allyl group such as Toruylile, etc., for example, cyclopropylcarbonyl, cyclobutylca Cyclo (lower) alkyl carbonyl groups such as rubonil, cyclopentyl carbonyl, and cyclohexyl carbonyl, examples Speaking of Glysil, Benzoyl Glysil, Tertiary Butoxy Calponil Daryl, Tertiary Butoxy Cal Bonyl Roysil An amino acid residue which may be protected with an amino group such as acetyl cyclyl, tertiary butoxycarbonyl histyl, etc., Bases, for example, methyl bases, vinyl bases, propyl bases, isopropyl bases '

Butylcalva Moir, Pentyl Carbour Moir, Isobutyl Carba Moir, Tertiary Butylkarva Moirile, Jimme Chill force, baile moir, methyl keru ba moir, methyl keiruka Lova's Moles, Methyl-Isoblobile Carno Moles, etc. Kilo carnoyl moieties, such as picoyl moieties, pyrrole moieties, thiazolyl methyl moieties Heterocyclic (lower) alkyl alkali such as moils, morpholino methyl carbs Moils, morpholino ethyl carbs Groups, for example, N—Picolyl N—Methyl Methyl Carbide, N—Pyrylene Rleux N—Methyl Carcinoid Mole, N 1-Morholinomethyl-N-Ethylcarbamoyl, N-Morholinomethyl-N-N-heterocycle, such as methylcarbamoyl (Low) Al Le-N—Lower-grade Alkali-powered bamboo moir bases, benzyl carir-ba-moles, fuel car no-moles, and benz hydra Al (lower) alkyl carba moyl groups, such as molybdenum moils, for example, N-benzyl-N—methyl carba moles,

N—N-methyl (N-methyl carbamol), N—N-methyl (N-methyl carbamoyl) N-lower alkyl N-phenyl, such as N-phenyl N-methylalbamol, etc. Alkaline carbohydrate moieties, such as mexican carbonyl methyl carba's moire, etoxycarbon melon carpa 'Moles, et al. Carbills, etc.' Low-grade Alkoxycarbonyl (lower) Alkyl Mobil, etc. Mobil, etc. Basically, for example, methoxymethyl carbamine, methoxymethylcarbamine, ethoxypropyl Alkoxy (Lower) Alkyl Alkali Mobil Base, etc., Benzir Kalba Moir, Toruil Kalpa Moi , Such as pyridyl molybdenum, molyholin molybdenum, and thiazolyl molybdenum Complex force such as yl-moiety, such as N-pyridyl-N-methyl-calvamoyl, N-thiazole-N-methyl N-heterocyclic N-lower alkyl group such as Lubamoyl

Heterocyclic carbonyl groups, more preferably, for example, morpholino carbonyl, thiomolino carbonyl, piperidino carbonyl Bonyl, 4-methyl 1-piperazine carbonil, 1, 2, 3, 6—Tetrahydro: I N-containing heterocyclic mono-N-arylcarbonyl group, for example, methoxycarbonyl group, even if it has been replaced with a lower alkyl group such as Ethoxybonbon, Propoxycarbonyl, Isobroxybonbon, Butoxykarbonil, Isobutoxy Low-grade aluminum such as carbonyl, tertiary butoxycarbonyl, pentoxycarbonyl, hexoxycarbonyl, etc. Koki Shirbon Units, for example, chloride ethoxycarbonyl, dichloroethoxycarbonyl, tricyclo mouth ethoxycarbonyl, triff Mono- (or di- or tri-) such as fluoromethoxycarbonyl: halo (lower) alkoxy carbonyl group, for example, hidden ROXY METAL BOX, DO π KEY SHOT BOX,

Hydroxy Propoxy Calbonil, Hydroxy Butoxy Hydroxy (lower) alcohol such as carbonyl, carbonyl group, for example, benzyloxy, carbonyl, and funneloxy Carbonil, 412 Tv Carbbon, Triloxy Carbbon, Benz Hydroloxy Carb Al (lower) alkoxy carbonyl groups such as vinyl, such as vinyloxycarbonyl, aryloxycarbonyl, etc. Alkoxy radical carbonyl group, for example, acetyl methyl carbonyl, propionyl meth oxycarbonyl, acetyl Lower-alkanol (lower) alkoxycarbonyl groups such as lutekoxybonyl, for example, mesyl, ethylsulphonyl, Pin ls e le e d le, Lee Seo blanking Russia pin ls e

_} Le Honi! Le, Butyresles Lehoniré, Isobutirez <> Lehoniré, Tertiary Butylsulhonir, Pentilsulhonir, Hexirul Examples thereof include lower alkyl sulfonyl groups such as honyl and the like, and arylsulfonyl groups such as phenylsulphonyl and tosyl.

Preferred “lower alkylthio groups” include methylthio, ethylthio, bromothio, isoprobiothio, and butylthio. Linear or branched alkylthio groups such as, isobutylthio, tertiary butylthio, pentylthio, hexylthio, etc. Among them, more preferred ones are: C 1 -C ₄ alkylthio groups.

As for the preferable “heterocyclic group” formed by R ¹ , R ² and the adjacent nitrogen atom, R ⁷ , R ⁸ and the adjacent dimension as exemplified above are preferred. Formed by nitrogen atoms What is necessary is just to refer to a heterocyclic group.

Preferred "hydroxy (lower) alkyl groups" include hydroxymethyl, hydroxyethyl, hydroxypropyl, and the like. Hydroxyisopropyl, hydroxybutyl and the like can be mentioned. Suitable “lower alkyloxy (lower) alkyl groups” include methoxymethyl, ethoxymethyl, methoxyethyl, ethoxy, and the like. Such as stil and methoxy propyl. Suitable salts of compound (I) are conventional non-toxic salts, for example, formates, citrates, trifluorophosphates, maleates, tartrates, metatrates Organic acid addition salts such as sulfonic acid, benzenesulfonate, and trifluoromethanesulfonate, for example, hydrochloride, hydrobromide, sulfate And inorganic acid-added salts such as formic acid salts, for example, salts with amino acids such as aspartate and glutamate. In this specification, the term "treatment" includes prophylactic treatment.

Specific examples have the good Ri good or that put into R ¹ or et R ^4, are shown below.

R ¹ is the formula

R

N-1 CO-1

R [Wherein, R ⁷ and R ⁸ are each hydrogen or lower alkyl.

C

Means a kill group, or

R ⁷ and R ⁸ are taken together with an adjacent nitrogen atom to form a morpholino group] and a group represented by the formula:

Five

R

N-one

R 6

Where R ⁵ is hydrogen or a formula

.7

R

9

N—CO— or R—CO

8 In the formula, R ′ and R ° together with an adjacent nitrogen atom form a morpholino group, and Represents a lower alkyl group.)

And R ⁶ represents a hydrogen or lower alkyl group.

A lower alkyl group substituted with a substituent selected from the group consisting of:

R ² is hydrogen or a lower alkyl group,

R ³ is hydrogen or lower alkyl group, and

R ⁴ is a lower alkyl group.

In particular, the most preferred compounds are

2 (S)-[Ν ^α- [2 (S)-{N-(2-morpholino-carbonyl)-N-methylamino-carbononi-ro 1-13 — phenylpropionyl] 100% ^α — methyl-L-histidine] amino 1-cyclohexyl 3 CS) — Hydroxy 6 — Methyl to butane or its hydrochloride, and

2 (S) — [Ν ^α — [2 (S) — [Ν — Methyl Ν —

[2-{N-(Morholino Carbonil) 1 N-Methyl Amino Acid] Aminocarboniloxy] 1-3-Fene [L-Bropionyl] 1: メ^α- Methyl-L-Histidyl] Amino 1-Cyclohexyl 3 (S)-Hydroxy 6-methylheptane or its hydrochloride.

Compound (I) may contain one or more stereoisomers based on an asymmetric carbon atom, and all of these isomers and mixtures thereof are described in the present invention. Included in the range.

In order to show the usefulness of the compound (I) in treating renal diseases, the results of pharmacological tests of representative examples of the compound (I) are shown below.

Test compound

(1) 2 (S) one [New ^alpha one [2 (S) - {New one (2 one molar Ho Li Bruno Ca Le ball double Le E Ji Le) Single N- main Chi le § Mi Bruno Ca Le Bo 2-phenylpropionyl] ^-α- methyl-L-histidine] amino 1-cyclohexane relay Three

C S) —Hydroxy 6—Methyl to butane hydrochloride

(2) 2 (S) — [— ^α — [2 (S) — [Ν — methyl ー one [2 — {N— (Morholino carbonyl) one N— methマミ 3 3 3 3 3 3 3-Hue Nylpropionyl] 100% ^α- Methyl L-Histidyl] Amino 1-Cyclohexyl 3 CS)-Hydroxy 6 One methyl heptane hydrochloride

(Α) Captobrill (control compound, angiotensin converting enzyme (ACE) inhibitor)

Test 1 (^ blood flow increasing effect)

Test method

Male and female cynomolgus monkeys (body weight: 2.0-4.8 kg) bred with a normal diet were administered subcutaneously with losemg losemg on the day before the administration of the test compound. In addition, 5 mg / kg of Fosemide was administered intravenously for use in the experiment. After anesthesia with pentobarbital (20 mg Z kg, intravenous administration), pentobarbital was continuously infused intravenously at a rate of 6 mg / kg / hour to maintain the anesthesia. Fix a force-sensitive monkey on the heat-retaining fixture and keep it warm at 37 ° .Insert a force nucleus for blood pressure measurement in the right femoral artery and a drug in the right femoral vein, and compress it in the left artery. A respiratory artery blood flow was measured with a magnetic flow probe and an electromagnetic blood flow meter. Blood pressure, heart rate and? ? After the arterial blood flow was sufficiently stabilized, the test compound dissolved in physiological saline was intravenously administered at a dose of 0.2 mlZ kg. Test results

Test 2 (diuretic effect)

Test method

Female quizarire (body weight 3.2.3.9 kg) was penetrated intravenously at a rate of 4 mg / kg / hour after penbital anesthesia (20 mgZ kg, intravenous administration). Anesthesia was maintained by continuous injection of valbital, and a continuous infusion was introduced into the right saphenous vein. Para-amino hippuric acid (20 mg / kg :) and inulin (50 mg / kg) were administered intravenously and immediately para-amino-hippuric acid (0.25%) was added. Physiological saline containing 0.1% vinulinine (0.1%) was continuously infused at a rate of 0.2 ml / kg / min. Under the blood pressure measurement, urine was collected from the bladder using a urine collecting device, and blood was collected from the right upper arm vein. After the urine volume and blood para-amino-hippuric acid and inulin concentrations are stable after 90 minutes, urine is collected every 45 minutes for 45 minutes before and 60 minutes after administration of the test compound after the concentration of the para-amino-hippuric acid and inulin is stabilized. And blood was collected. The amount of urine and the mass of the electrolyte were measured, and the obtained blood and urine samples were measured for Ramino hippuric acid and inulin level. The renal plasma flow rate and glomerular flux were determined from the measured values. Test result (control: 100%)

Shows each increase rate 15 minutes after administration of test compound

Test 3 (Acute toxicity test)

Test method

Five male rats and five female rats (Crj: CD (SD) strain) were grouped. The test compound was dissolved in physiological saline to adjust to each concentration, and administered intravenously to a rat, followed by observation for 14 days. The LDC ₍₎ value is calculated by the probit method. Test results

As is clear from the above test results, compound (I) has an effect of increasing renal blood flow and a diuretic effect, such as ^ insufficiency, glycemic nephropathy, nephritis (eg, For example, glomerulonephritis), nephrotic syndrome, nephrotoxicity due to drugs, renal edema, gout, hyperuricemia and other renal diseases.

Compounds (I) of this invention may also include, for example, hyperaldosteronism, myocardial infarction, cardiac hypertrophy, angina, Bartter's syndrome,? 1 Tumors, cerebrovascular disorders, central nervous system (CNS) involvement (eg, Alzheimer's disease, depression, etc.), and vascular diseases associated with diabetes (eg, diabetic neurology) Pathology, diabetic retinopathy, etc.), psoriasis, cutaneous sclerosis, intracellular homeostasis, and diseases caused by retroviruses (eg, AIDS, HIV May be useful in the treatment of other diseases such as virus infections :), and to measure the presence of renal disorders such as hypertension It is useful as a diagnostic agent.

The compound (I) or a salt thereof used as an active ingredient of a pharmaceutical composition can be used in mammals including humans, in cabules, tablets, tablets, Granules, powders, lozenges, Oral, non-oral or external (topical) administration in the form of pharmaceutical preparations for use such as pills, softeners, suppositories, injections, suspensions, syrups, etc. I can do it.

The above pharmaceutical preparations include, for example, sucrose, starch, mannite, sorbitol, lactose, glucose, cellulose, talc, Excipients such as calcium phosphate and calcium carbonate, for example, cellulose, methylcellulose, hydroxymethylcellulose Binders such as polystyrene, polypyrrolopyrrolidon, gelatin, arabic rubber, polyethylene glycol, sucrose and starch; For example, starch, carboxymethylcellulose, hydroxypropyl starch, sodium hydrogen carbonate, calcium phosphate, citrate Disintegrators such as calcium, for example, magnesium stearate, air-sealed shell, talc, sodium rauryl sulfate Lubricants such as um, for example, flavoring agents such as citric acid, menthol, glycin, orange powder, etc., for example, sodium benzoate, sodium bisulfite Preservatives such as trium, methylno, raben, brovirno, raben, etc., for example, cinnic acid, sodium citrate, acetic acid, etc. Stabilizing agents, for example, suspending agents such as methylcellulose, polyvinylpyrrolidone, aluminum stearate, etc. Dispersing agents such as roxiv π-pill methylcellulose, for example, diluents such as water, for example, cacao noter, white petrolatum, polyethylene glycol The base can be manufactured by conventional methods using various kinds of organic or inorganic carriers used in the preparation of pharmaceuticals such as waxes. The amount of the active ingredient in the pharmaceutical composition is It may be in an amount sufficient to produce the desired therapeutic effect, for example, from about 0.2 mg to about 500 mg per oral or non-oral unit dose.

The active ingredient can usually be administered in a unit dose of 0.1 mg / individual to 500 mg / Z 1 to 4 times a day. However, the above dosages may be adjusted as appropriate according to the patient's age, weight, symptoms, or administration.

Examples of the formulation of the present invention are shown below.

Example 1

Test compound (1) 5 mg

Lactose 80 mg

Mix the above ingredients and fill it with ordinary hard gelatin capsule to make a capsule.

Example 2

Test compound (2) 5 mg

Lactose 65 mg

The above components are mixed, and the mixture is added to a normal hard gelatin capsule to obtain a capsule agent.

Claims

Expression

Rag H—R

Η

[Wherein, R ¹ is an acyl group, a hydroxy group, a lower alkoxy group, an aryl group, a lower alkylthio group and a formula

Ichino ⁵

6

R

(Wherein, R ⁵ represents a hydrogen or an acyl group, and R ⁶ represents a hydrogen or a lower alkyl group, respectively) selected from the group consisting of: A lower alkyl group which may be substituted with a substituted group; an aryl group; or a lower alkyl group and an acyl group. An amino group which may be replaced by a selected substituent;

R ² represents hydrogen or a lower alkyl group, or R ¹ and R ² together with an adjacent nitrogen atom form a lower alkyl group, Head mouth (lower) alkyl group, lower alcohol (lower) alkyl group, acyl (lower) alkyl group, oxo group, and acyl group Selected from the group Forming a heterocyclic group which may be substituted with a substituent, R ³ is hydrogen or a lower alkyl group,

R ⁴ represents a lower alkyl group], or a compound thereof or a salt thereof as an active ingredient.

2. In the compound described in claim ¹ , R ¹ is a group represented by the formula:

R

N-1 CO-1

R Z

[Wherein, R ⁷ and R ⁸ each represent hydrogen or a lower alkyl group, or

R ⁷ and R ⁸ together with the adjacent nitrogen atom form a morpholino group.]

Where R is hydrogen or a formula

R

N— CO— or R ⁹ — CO—

R

': In the formula, R ⁷ and R ⁸ together with the adjacent nitrogen atom form a morpholino group, and R ⁹ represents a lower alkyl group :) And R ⁶ represents a hydrogen or lower alkyl group.

The compound according to claim 1, wherein R ² contains a compound in which hydrogen or a lower alkyl group is an effective component. ? Disease treatment agent.

3.2 (S) -1 [N-one [2 (S)-{N- (21-mol-holino-carbonyl) -N-methyl-amino-carb] Le O key sheet} one 3 - full et two Le Bed b peak for two relay] one New ^alpha - main Chi le over L one heat scan Chi di le] A Mi Roh -1-Shi key sheet Le -3 to click b (CS) monohydroxy 6—The therapeutic agent for ^ disease according to claim 2, which contains methylbutane or a hydrochloride thereof as an active ingredient.

. 4 2 (S) - [ N a - [2 (S) - [Ν- methyltransferase one Ν one [2 - {N- (molar e Li Bruno Ca Le ball D Le) Single N- main Ji Le § Mi Roh} e Chi le] § Mi Roh mosquito Le ball double Le O key sheet] one 3 - off et two / Les blanking port pin for two Le] one N ^a - main Chi le over L one heat scan Chi di le] Amino 1-cyclohexyl-3 CS)-Hydroxy-1 6-Methylheptane or its hydrochloride as an active ingredient Claims Item 4. The therapeutic agent for renal disease according to Item 2.

5. Formula:

[Wherein R 丄 is an acyl group, a hydroxy group, a lower alkyloxy group, an aryl group, a lower alkylthio group, and a compound represented by the formula

6

R

C in the formula. Represents hydrogen or an acyl group, and R ⁶ represents hydrogen or a lower alkyl group, respectively.) Is a substituent selected from the group consisting of: Selected from the group consisting of a lower alkyl group which may be substituted with a group; an aryl group; or a lower alkyl group and an acyl group. An amino group; 0 R ² represents hydrogen or a lower alkyl group, or

R ¹ and R ² are taken together with the adjacent nitrogen atom to form a lower alkyl group, a hydroxy (lower) alkyl group, a lower akoxy (lower) Alkyl, acyl (lower) Alkyl, oxo, and acyl selected from the group consisting of: s: substituted with an anonymous group Form a heterocyclic group, R ³ is hydrogen or a lower alkyl group,

R ⁴ represents a lower alkyl group.) Or a salt thereof, which is a pharmaceutically acceptable substantially non-toxic carrier or excipient. A pharmaceutical composition for treating renal disease, which is contained together with a formulation.

6. In the compound described in claim 5, R ¹ is a compound of the formula:

7

R

: N—CO

R

[Wherein, R ⁷ and R ⁸ each represent hydrogen or a lower alkyl group, or

R ⁷ and R ⁸ are taken together with the adjacent nitrogen atom to form a morpholino group.]

.Five

R \ N one

R Z where R. Is hydrogen or a formula

— CO— or R '■ CO—

(Wherein, R ⁷ and R ⁸ form a morpholino group together with an adjacent nitrogen atom, and R ⁹ represents a lower alkyl group.)

And R ° is hydrogen or lower alkyl. Means group

A lower alkyl group substituted with a substituent selected from the group consisting of

The pharmaceutical composition according to claim 5, wherein the pharmaceutical composition contains a compound in which R ² is hydrogen or a lower alkyl group as an active ingredient.

7.2 (S)-[Ν ^α 1 [2 (S)-{N 1 (2-morpholinocarbonylethyl) -1 N-methylaminocarbonyl] 1- 3 — phenylpropionyl] 100- ^α- methyl: L-histidyl] amino 1-cyclohexyl 3 CS) —The pharmaceutical composition according to claim 6, which comprises hydroxy-6-methylbutane or a hydrochloride thereof as an active ingredient.

8.2 (S)-[N ^a- [2 (S)-[Ν-methyl relay Ν [2-{N one (morpholino carbonyl) one N-methyl] § Mi Roh} e Chi le] § Mi Roh mosquito Le ball double Le O key sheet] one 3 - full et two Le profile Pi o d le] one N ^a - main Chi le over L one heat scan Chi di le] Amino 1-cyclohexyl 3 (S)-Hydroxy 1-methyl hebutane or its hydrochloride as an active ingredient The pharmaceutical composition according to claim 6.

9. For the manufacture of a medicament for the treatment of kidney disease in humans or animals.

Expression:

(Wherein, R ⁵ represents hydrogen or an alkyl group, and R ⁶ represents hydrogen or a lower alkyl group, respectively). A lower alkyl group which may be substituted by a substituted group; an aryl group; or a group consisting of a lower alkyl group and an acyl group. Substituted with a substituent selected from the above;

2 means hydrogen or a lower alkyl group, or R ¹ and R ² together with an adjacent nitrogen atom form a lower alkyl group, D mouth (lower) alkyl group, lower alkyl (lower) alkyl group, acyl (lower) alkyl group, oxo group and acyl group A heterocyclic group which may be substituted with a substituent selected from the group consisting of R ³ , R ³ is hydrogen or lower alkyl, R ⁴ represents a lower alkyl group]

Use of a compound represented by or a salt thereof.

10. In the compound according to claim 9, R ¹ is a group represented by the formula:

R

N-1 CO-1

R

[Wherein, R ⁷ and R ° each represent hydrogen or a lower alkyl group, or

Groups and formulas represented by

[Wherein, R ⁵ is hydrogen or a formula

R

N—CO— or R—CO—

R

(In the formula, R ⁷ and R ⁸ together with an adjacent nitrogen atom form a morpholino group, and R means a lower alkyl group.)

And R ⁶ represents hydrogen or a lower alkyl group.]

Substituted with a substituent selected from the group consisting of: Is a lower alkyl group

R ² s is Ru lower A Le key Le group der compound was hydrogen or Use according to Claim 9.

11.2 (S) 1 [一^α 1 [2 (S) 1 {N 1 (21 morpholino carponyl ethyl) 1-N-methylamine 1-3-Ferro-bropionyl] ^-α- Methyl-L-Histidyl] Amino 1-Cyclo-3 CS ) — Hydroxy 6 — Use of methyl hebutane or its hydrochloride as defined in claim 10.

12. 2 (S)-[N ^a- [2 (S) — [Ν-Methyl Ν [[2-{N モ (Morholinocarbonyl) N N-Methyl § Mi Roh} e Chi le] § Mi Roh mosquito Le ball double Le O key sheet] one 3 - full et two Le profile Pi o d le] one N ^a - main Chi le over L one heat scan switch Jill] a Minnow 1-cyclohexyl-1 (S) -hydroxy 61-Methylheptane or its hydrochloride, as described in claim 10.

13. Expression:

[Wherein, R ¹ is an acyl group, a hydroxy group, a lower alkoxy group, an aryl group, a lower alkylthio group and a formula ■ N

ヽ⁶ (wherein, R ⁵ represents hydrogen or an acyl group, and R ⁶ represents hydrogen or a lower alkyl group, respectively) selected from the group consisting of: A lower alkyl group which may be substituted with a substituted substituent; an aryl group; or a group consisting of a lower alkyl group and an acyl group. Replaced by a substituent selected from the group consisting of: an amino group;

R ^{水素} represents hydrogen or a lower alkyl group, or R ¹ and R ² together with an adjacent nitrogen atom form a lower alkyl group, Hydroxy (lower) alkyl group, lower alkyl (lower) alkyl group, acyl (lower) alkyl group, oxo group, and Forms a heterocyclic group which may be substituted with a substituent selected from the group consisting of

R ⁴ represents a lower alkyl group]

The administration of a compound or salt thereof to a human or animal? ? Disease treatment ¾Methods.

14. The compound according to claim ¹³ , wherein R ¹ is a group represented by the formula:

R

Ν 一 CO 一

R 8

[Wherein, R and R ⁸ each represent hydrogen or lower alkyl 、, or R ⁷ and R ⁸ together form an adjacent nitrogen atom to form a morpholino group.

Groups and formulas represented by

R \ N one

R Z

[Wherein, R ⁵ is hydrogen or a formula

R \ N— CO- or R ⁹ — CO—

R Z

(Wherein R ⁷ and R ° together with the adjacent nitrogen atom form a morpholino group, and R. means a lower alkyl group)

And R ⁶ represents a hydrogen or lower alkyl group.]

A lower alkyl group which is replaced by a substituent selected from the group consisting of:

14. The therapeutic method according to claim 13, which comprises administering a compound in which R ² is hydrogen or a lower alkyl group.

15. 2 (S) - [N a one [2 (S) - ί Ν - (2 - molar E Li Bruno Ca Le ball double Le E Ji Le) Single Ν- main Chi le § Mi Roh mosquito Le Bo two 1 3 — phenylpropionyl] 1 ^α — methyl 1 L 1 histidyl] amino 1-cyclohexyl 3 CS ) -Hydroxy-6-methyl according to claim 14 which comprises the administration of butane or its hydrochloride to methyl. Treatment.

16. 2 (S) — [N ^a — [2 (S) — [N— Methyl N-1 [2 — {N — (Morholinocarbonyl) – N _ Methyl § Mi Roh} E Chi le] a Mi Roh mosquito Le ball double Le O key sheet] one 3 - full We two Le profile Pi o d le] one N ^a - main Chi le over L one heat scan Chi di le] Amino-1-cyclohexyl 3 CS)-hydroxy 1 6-can be obtained by administering butane or its hydrochloride to methyl 15. The treatment method according to claim 14.